Keywords

A 58-year-old female presented with diffuse thinning of her hair on the scalp. She reported gradual thinning of her hair over the past 5 years. Of note, her family history was significant for hair loss with her father and paternal grandfather. She denied hair loss of the eyebrows, eyelashes, or other body hair.

On physical examination, diffuse non-scarring alopecia was noted with retention of hair on the frontal scalp line (Figs. 1.1 and 1.2). Eyelashes and eyebrows appeared intact. A scalp biopsy was performed and revealed miniaturization of the hair follicles. Fingernails were normal in appearance.

Fig. 1.1
A photograph of a person's head with diffuse thinning of the scalp and widened mid-line part.

Diffuse thinning of the scalp with widening of the mid-line part. Image courtesy of Dr. Melissa Piliang and Janine Sot, MBA medical photographer

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Fig. 1.2
A photograph of a person's head with diffuse thinning scalp hair.

Diffuse thinning of the scalp with retention of the frontal scalp line. Image courtesy of Dr. Melissa Piliang and Janine Sot, MBA medical photographer

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Based on the clinical case description, what is the most likely diagnosis?

  1. 1.

    Diffuse alopecia areata

  2. 2.

    Drug-induced alopecia

  3. 3.

    Androgenetic alopecia

  4. 4.

    Telogen effluvium

Diagnosis

Androgenetic alopecia.

Discussion

Androgenetic alopecia (AGA) is a form of non-scarring alopecia caused by an excessive response to androgens [1]. This progressive type of hair loss is common in both men and women, affecting up to 80% of men and 50% of women over the course of their lifetime [2]. Although prevalence data is limited, AGA is most prevalent in Caucasian populations, as up 50% of Caucasian men will have AGA by age 50 [3]. Asian and African populations also have high prevalence rates but to a lesser degree when compared to Caucasian populations [4].

Presentations of AGA differ between sexes with men initially experiencing recession of the frontal hairline and increased loss in the temporal regions. This may be accompanied by hair loss at the vertex creating a characteristic “horseshoe” pattern [5] (Fig. 1.3). In women, the pattern of hair loss is not as distinct as in men; it generally consists of diffuse thinning at the crown with a presenting concern of a widening center hair part [6] (Fig. 1.4).

Fig. 1.3
A set of two photographs of the head of a person. It displays the frontal hairline with hair loss on the vertex scalp.

Presentation of AGA in males with recession of the frontal hairline as well as hair loss at the vertex, creating a “horseshoe” pattern. Images courtesy of Dr. Melissa Piliang and Janine Sot, MBA medical photographer

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Fig. 1.4
A set of four illustrations of both male and female. It explains the four stages of hair loss in the midline part of the head.

Comparison of the differing presentations of AGA between men and women. The top panel depicts the hair loss pattern seen in men with recession of the frontal hairline and increased loss in the temporal regions. The bottom panel illustrates the diffuse thinning at the crown and widening center part found in women with AGA

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Predisposition to AGA is likely multifactorial caused by the interaction of several genes and environmental factors with the risk of developing AGA dramatically increasing when there is a positive family history [7, 8].

As the name suggests, AGA is driven by androgens. Androgens are important regulators of human hair growth. Under baseline conditions, androgens stimulate thin hairs that lack pigment, vellus follicles, to transform into thicker, pigmented, terminal hair follicles [9]. This stimulation of hair growth is most evident during adrenarche when circulating levels of androgens increase resulting in the manifestation of pubic and axillary hair in both sexes. These androgen-stimulated hairs are unlike the terminal hairs found on your head, eyelashes, and eyebrows that can grow constitutively in the absence of androgens [10]. In those with AGA, androgens may have a paradoxical effect on some areas of the scalp and cause dark terminal hair follicles to regress to fine and colorless vellus hairs. This phenomenon is believed to be a result of an imbalance of androgen production and degradation, as well as an increase in the number of androgen receptors [11, 12].

The androgens, dihydrotestosterone (DHT), and nuclear lipophilic enzyme, 5α-reductase are thought to play an important role in the pathophysiology of AGA. In humans, DHT is made from testosterone via the enzyme, 5α-reductase [13, 14]. 5α-reductase has two isoforms (Type I and Type II) in scalp hair follicles [13, 14]. Type II 5α-reductase is a chief mediator of DHT production in the scalp, as it contributes to 80% of DHT production from testosterone [15]. Studies have demonstrated that men with AGA have amplified expression of Type II 5α-reductase and consequently elevated concentrations of DHT and androgen receptors [15]. This proves to be the crux of the pathology of AGA, as DHT and 5α-reductase cause a reduction in hair follicles by shortening certain phases of the hair follicle growth cycle [16, 17]. Normally, hair follicles undergo continual phases of growth and development (anagen), regression (catagen), and rest (telogen), but in those with AGA, the anagen phase is shortened. This results in a smaller anagen-to-telogen ratio and ultimately leads to follicular shrinkage and a decrease in overall hair coverage on the scalp [14] (Fig. 1.5).

Fig. 1.5
An illustration of a network diagram for hair loss.

The multiple effects DHT has on hair follicles: Testosterone is converted into DHT by Type II 5ɑ-reductase. In individuals with AGA, there are increased levels of the Type II isoform of 5ɑ-reductase resulting in elevated levels of DHT. DHT, in turn, erodes the subcutaneous fat. Additionally, DHT shortens the duration of the hair growth cycle. The lack of subcutaneous fat and shortened hair cycle prevents hair follicles from growing to their full size. The hair shaft is eventually lost after multiple cycles of hair follicle miniaturization

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The diagnosis of AGA is usually made from the history and clinical findings alone. A thorough history should be elicited to rule out other potential causes of hair loss. The physical exam findings are also imperative for the diagnosis of AGA. The pattern of hair loss described above as well as a negative hair-pull test would suggest AGA instead of telogen effluvium [18]. In women, a complete hormonal evaluation may not be necessary if other signs of androgen excess are not present such as menstrual irregularities, hirsutism, severe cystic acne, virilization, or galactorrhea [19]. If a scalp biopsy is required, the morphological changes are subtle and vary with the stage of AGA. In the early phases, there is a mononuclear inflammatory infiltrate centered at the junction of the follicular infundibulum and the associated sebaceous duct [5]. As AGA progresses, terminal hairs become replaced by vellus or rudimentary anagen hair follicles [5]. Areas of the scalp with well-established androgenetic alopecia show pronounced miniaturization of hair follicles and complete zones of terminal hair replacement by vellus hairs [5].

Treatment

AGA may have a dramatic psychosocial impact and therapeutic intervention may be desired to assist the patient. The goal of AGA treatment is to increase hair growth and impede the progression of hair thinning.

Minoxidil has been a reputable treatment for AGA for over 30 years. Although knowledge of the entire mechanism of action has not yet been elucidated, conversion of minoxidil to its active derivative minoxidil sulphate by follicular sulfotransferase is key to minoxidil’s effectiveness. Animal studies have demonstrated that with topical application, minoxidil results in hair follicles remaining in the anagen phase for a longer duration as well as reducing the time spent in the telogen phase [20]. Side effects associated with topical application of either the 2% or 5% formulation of minoxidil are dermatitis, headaches, and hypertrichosis [21]. Another pitfall with topical minoxidil is compliance as peak efficacy is achieved with consistent application of the product. Oftentimes, premature discontinuation of treatment occurs due to a lack of perceived efficacy, adverse effects, or altered hair texture. As a result, a 2019 study compared the efficacy of oral and topical minoxidil in the treatment of female-pattern hair loss. Groups were treated with either 1 mg of oral minoxidil or 5% topical minoxidil solution for 24 weeks. The results showed that low-dose oral minoxidil provides improvement with female-pattern hair loss, but the results did not differ from topical minoxidil 5% solution [21].

Another highly-regarded treatment option for AGA is the use of oral finasteride, which exerts its effects on Type II 5-alpha-reductase by inhibiting the conversion of testosterone to DHT. Finasteride at a 1 mg dose was approved by the FDA for men with AGA in the late 1990s and has shown great potential for the treatment of female pattern hair loss [16]. It is important to note that despite finasteride’s potential teratogenic effect in women of childbearing potential, recent publications have demonstrated positive findings of increased hair density in pre- and post-menopausal women who are not at risk of these side effects [22]. Finasteride only inhibits Type II 5α-reductase while dutasteride, another 5α-reductase inhibitor, blocks both Type I and Type II isoforms [15, 16]. Studies have shown that dutasteride has superior efficacy compared to its predecessor finasteride in promoting hair growth [23].

In women, oral antiandrogens such as spironolactone are often used to treat AGA. Spironolactone, a potassium-sparing diuretic, is also a weak partial agonist to the androgen receptor. Through the weak partial agonist action, spironolactone blocks the more potent DHT and free testosterone from interacting with the androgen receptor [24]. Additionally, spironolactone inhibits androgen synthesis and enhances the conversion of testosterone to estradiol [24].

Other medications such as ketoconazole 2% shampoo demonstrate positive findings in the treatment of AGA, but it is not currently FDA approved for its use [25]. In combination with oral finasteride, this antifungal has been shown to increase hair density and the amount of anagen hair follicles in those with AGA by blocking the production of testosterone [26].

Platelet-rich plasma (PRP) and low-level laser therapy (LLLT) have also exhibited positive potential in treatment for those with AGA [27, 28]. PRP is a non-invasive treatment where a patient’s blood is collected in the office and centrifuged to separate platelet-rich plasma. The plasma is then re-injected into an area of target treatment or applied through a microneedling technique. LLLT is considered less invasive as it uses laser light to encourage hair follicle growth [29]. There are several FDA-approved LLLT devices for AGA including: HairMax Lasercomb, Capillus Pro, and iGrow Hair Growth System. All these devices assist in hair regrowth via the stimulation of mitochondrial hair follicle stem cells [29, 30].

Currently, there are investigations into the use of Janus kinase (JAK) signal inhibitors for alopecia areata with promising results. As a result, researchers are hypothesizing similar results with AGA [31]. Further studies into the use and efficacy of PRP, LLLT, and JAK inhibitors would need to be conducted to determine their efficacy and role in the treatment of AGA.

Key Points

  • Current research suggests increased androgen receptors and imbalanced androgen production/degradation is responsible for the pathology seen in AGA.

  • Finasteride, in combination with topical minoxidil, are first-line, FDA-approved treatment for men with AGA while women may use topical minoxidil in combination with oral spironolactone.

  • Topical ketoconazole, while not FDA-approved, has shown promising effects in the phenotypic appearance of those with AGA when used in combination with finasteride.

  • Platelet-rich plasma (PRP) has recently gained popularity as an effective treatment for AGA.

  • Recent clinical trials of JAK inhibitors demonstrate potential for hair regrowth in AGA.